Chromosome translocations are frequently associated with many types of blood cancers and childhood sarcomas. Clinically, chromosome translocations are important because they offer the ability to precisely diagnose the type of cancers and to tailor treatment. Paradoxically, the molecular mechanism that leads to chromosome translocations is not well understood. The available evidence suggests the role of process repairing DNA double strand breaks in the formation of chromosome translocations. Recently, we developed a novel yeast-based model system to detect non-homologous end joining (NHEJ)- dependent, reciprocal chromosome translocations in vivo. This system allowed us to detect in real time a reciprocal translocation of site-specific DNA double strand breaks from a population of cells. A screen using our system resulted in the identification of several gene mutations that elevate the frequency of NHEJ- dependent chromosome translocations. Through this system, we uncovered a role of a specific DNA damage surveillance pathway in suppression of chromosome translocations. The focus of this proposal is to identify and characterize the genetic network that suppresses chromosome translocation. An approach combining genetics, cell biology and biochemistry will be used to provide mechanistic insights into genetic and mechanistic underpinnings of NHEJ-mediated chromosome translocations. These studies will shed light on the molecular mechanism leading to chromosome translocations in humans and may provide conceptual basis for advanced therapeutics to treat or prevent blood cancers. PUBLIC HEALTH RELEVANCE: The long-term objective of our research program is to dissect the molecular mechanism that causes oncogenic chromosome translocations. Mutations of genes identified by our study are known to enforce one of the DNA damage surveillance pathways, which can suppress chromosome translocations, and predispose patients to chromosomal translocations and lymphoid malignancy. This application will identify and characterize damage- surveillance and other mechanisms that suppress chromosome translocation to understand the defects in blood cancers and develop novel preventive and/or therapeutic strategies.